Volume 135

Belzutifan, a novel orally bioavailable small-molecule inhibitor of hypoxia-inducible factor 2α (HIF-2α), represents a mechanistically distinct and clinically promising therapy for clear cell renal cell carcinoma (ccRCC), particularly in patients with von Hippel–Lindau (VHL) disease. By selectively disrupting the VHL–HIF–2α signaling axis, Belzutifan effectively inhibits hypoxia-driven transcriptional programs that promote tumor progression. Unlike traditional therapies such as VEGF inhibitors and immune checkpoint blockade, Belzutifan directly targets a core oncogenic pathway unique to VHL-deficient tumors. Clinical trials have demonstrated encouraging response rates and manageable safety profiles, both as monotherapy and in combination with agents like cabozantinib. However, emerging resistance, limited efficacy in pre-treated populations, and concerns about long-term toxicity highlight areas that require further investigation. This article reviews the underlying molecular mechanism, clinical trial data, therapeutic advantages, and key limitations of Belzutifan, while also exploring its future potential in broader contexts of renal cell carcinoma and in rational combination strategies.

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